Method for treating ischemic conditions

ABSTRACT

A method is disclosed for treating an ischemic condition. The method comprises coadministering topically and internally a vasodilator to a patient having the condition for treating the condition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.06/463,593 filed on Feb. 3, 1983, now U.S. Pat. No. 4,650,484 whichapplication Ser. No. 06/463,593 is a continuation of U.S. patentapplication Ser. No. 06/285,862 filed on July 22, 1981 now abandoned.These applications are incorporated herein by reference and benefit isclaimed of their filing dates. These applications are assigned to ALZACorporation of Palo Alto, Calif.

FIELD OF THE INVENTION

This invention pertains to a method for the management of ischemicconditions including angina pectoris by administering topically andinternally a vasodilator drug to a symptomatic patient.

BACKGROUND OF THE INVENTION

Vasodilator drugs are the mainstay in the symptomatic treatment ofischemic conditions including angina pectoris. Patients afflicted withthese conditions, especially angina pectoris, may require almostimmediate therapeutic response to a vasodilator drug for relief frompain, and in some instances fright, or patients with angina pectoris mayrequire a continuous therapeutic response to a vasodilator drug todecrease the frequency and severity of attacks. Consequently,vasodilator drugs frequently are administered sublingually because thismethod provides a rapid onset of therapeutic effect and accompanyingimmediate relief of symptoms; also vasodilator drugs are frequentlyadministered orally because this method provides a longer duration ofaction for alleviating clinical symptoms and can provide prophylacticbenefit.

While the above methods of administration provide needed benefits, thereare disadvantages associated therewith. For example, sublinguallyadministered vasodilator drugs have a brief duration of action making itnecessary for some patients to take many doses, and orally administeredvasodilator drugs often are used in high doses, they are erraticallyabsorbed into the systemic circulation, and do not provide continuoustherapy.

OBJECTS OF THE INVENTION

Accordingly, it is an immediate object of this invention to provide botha novel and useful method for treating ischemic conditions includingangina pectoris, which method overcomes the disadvantages known to theprior art.

Another object of the invention is to provide a method for treatingischemic conditions including angina pectoris, which method comprises acombination of administering a vasodilator drug topically and internallyto a patient in need of such treatment.

Another object of the invention is to provide a method for treatingischemic conditions including intractable angina pectoris which methodcomprises administering a vasodilator drug topically and concomitantlyinternally to produce clinically satisfactory results.

Yet still another object of this invention is to provide a method fortreating angina pectoris in a human afflicted with same by administeringa vasodilator drug or different vasodilator drugs topically andsimultaneously internally for obtaining clinical and therapeuticefficacy in treating angina pectoris.

Yet another object of this invention is to provide a method forlessening the incidence of anginal attacks by administering at least onevasodilator drug in a therapeutically effective amount topically andinternally for producing the intended result.

Other objects features and advantages of this invention will be moreapparent to those skilled in the art from the detailed description ofthe invention, and the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1, 2, and 3 show bandages according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of the invention, there is provided amethod comprising administering a vasodilator drug in a therapeuticallyeffective and beneficial amount both topically and internally to a humanpatient over time. The method comprises coadministering the vasodilatorsimultaneously topically and internally, topically then internally,internally then topically, multiple administrations topically andinternally, multiple administrations internally and topically, and thelike.

The term topically as used herein, denotes administering to the skin ofa patient in need of a vasodilator drug, the drug for percutaneouspassage of the vasodilator into the systemic circulation of the patient.The skin sites include anatomic regions for transdermally administeringthe drug as represented by the forearm, abdomen, chest, back, buttock,mastoidal area and the like. The vasodilator is administered to the skinby placing on the skin a bandage that administers the vasodilator, andwhich bandage is designed, shaped, sized, and adapted for easy placementand comfortable retention on the skin.

The term internally as used herein, denotes administering thevasodilator orally into the gastrointestinal tract, administering thevasodilator into the mouth such as buccally to the inner surface of thecheeks, and sublingually beneath the tongue. The vasodilator can beadministered internally in pharmaceutical formulations expressed astablet, sustained release, pellet, capsule, solution, suspension, andthe like.

The phrase vasodilator drug, and the term vasodilator as used hereindenotes vasodilators including nitrites, nitrates and their esters, suchas their esters of sugars and polyols. The vasodilators genericallypossess a member selected from the group consisting of ONO, and ONO₂.The vasodilators include amyl nitrite, ethyl nitrite, glyceryltrinitrate, also known as nitroglycerin, nitroglycerin absorbed onlactose such as 1 to 30% nitroglycerin on 99 to 70% lactose, preferrably10% nitroglycerin and 90% beta-lactose, or optionally on alpha-lactose,octyl nitrite, sodium nitrite, clonitrate, erythrityl tetranitrate,isosorbide dinitrate, mannitol hexanitrate, pentaerythritoltetranitrate, penetrinitol, triethanolamine trinitrate, trolnitratephosphate (triethanolamine trinitrate diphosphate), propatylnitrate, andthe like.

The expression ischemic conditions as used herein generically denotesconditions that respond to vasodilator therapy through hemodynamicresponse and the like. The condition includes vasodilators used torelieve pain in the treatment of its most common clinical expressionangina pectoris, as a prophylactic for the prevention of angina pectorisand in hypertension, for the relaxation of the involuntary muscles ofthe blood vessels mainly the arteries and arterioles, for increasingoxygenation from vasodilation, mainly for increasing the supply ofoxygen to the heart, for improving exercise performance, in thepharmaco-prevention of coronary disease, for increasing the circulationin the vascular bed for warming cold fingers and toes and for treatingfrostbite. The vasodilators and their uses are known in Cutting'sHandbook of Pharmacology, Sixth Edition, Chapter 24, 1979, published byAppleton-Century-Crofts, New York.

The medical bandage useful for the present purpose can have variousshapes, such as oblong, square, round, rectangular, and the like.Medical bandages that can be used for the present purpose are seen inFIGS. 1, 2 and 3. In FIG. 1, medical bandage 10 is seen in openedsection, and it comprises a backing member 11 that defines one face ofbandage 10, and a reservoir 12, containing vasodilator drug 13.Reservoir 12 has a surface in contact with backing member 11 and asurface in contact with release rate controlling membrane 14. Backingmember 14 is formed of occlusive or non-occlusive materials, and it isessentially impermeable to passage of components contained in bandage10. Reservoir 12 is a mass transfer conductor and it is formed of amaterial that can contain from 5 mg to 750 mg of vasodilator to ratecontrolling membrane 14 for release of vasodilator 13 from device 10.Materials suitable for forming reservoir 12 include solid materials suchas synthetic and naturally polymeric materials, including polyolefins,polyacrylic acids, polysilicones, copolymers of olefins, esters ofolefinic acids, waxes and the like. Rate controlling membrane 14 isformed of a material that permits the passage of drug by diffusion, orit is formed of a microporous material. Materials that permit thepassage of vasodilator drugs include polymers such as polyolefins,polydimethylsiloxanes, copolymers of ethylene-vinyl acetate, microporouspolycarbonates, microporous polysulfones, and the like. The bandage isused by applying it directly to the skin for releasing a therapeuticallyeffective amount of vasodilator to the skin. The bandage can be held onthe skin by a thin film of non-toxic adhesive, by adhesive along theperimeter of the release rate membrane, or by mechanical means such astaping it to the skin. Procedures for manufacturing the medical bandageare disclosed in U.S. Pat. No. 3,598,122; 3,742,951; 3,996,934; and4,031,894.

Another medical bandage that can be used for the present purpose is seenin FIG. 2. In FIG. 2, bandage 20 is seen in opened section, and itcomprises a backing member 21 that serves as a protective cover and itis made of a material, or a combination of materials, or a laminate,which in any instance is impermeable to the passage of components inbandage 11. Typical materials for forming backing member 21 include highdensity polyethylene, metal foil, a laminate of a lamina of polyethylenein laminar arrangement with a lamina of aluminizedpolyethylene-terephthalate and a lamina of ethylene-vinyl acetatecopolymer, or a laminate comprising a lamina of aluminizedpolyethylene-terephthalate, a lamina of ionomer and a lamina ofethylene-vinyl acetate copolymer.

A reservoir 22 is adjacent to backing member 21 and immediately belowone surface 23 of backing member 21. Reservoir 22 bears on its surfacedistant from backing member 21 a membrane 24 for controlling the releaseof vasodilator drug 25 from medical bandage 20. Reservoir 22 is formedof a gelled fluid 26 having a low to high viscosity. Reservoir 22 ispreferrably made as a continuous phase and it contains rheology agent 27with vasodilator dispersed throughout the reservoir. In bandage 20,outer edges 28 of backing member 21 can overlay edges 19 of reservoir 22and in this manufacture they will join edges 29 of membrane 24 in fluidtight arrangement. The sealed reservoir is made by pressure sealing,fusion, adhesion, or through an adhesive applied to the edges ofcontacting members. Medical bandage 20 is held on the skin of a human bya layer of adhesive, or optionally an adhesive that extends around theouter perimeter of membrane 24, or by mechanical means such as a stripof tape. Reservoir 22 contains about 5 to 750 mg of vasodilator, that issupplied in a dosage unit amount of drug 25 to release rate controllingmembrane 24 throughout the medical history of bandage 20.

Generally, the dosage amount in a medical bandage used for the presentpurpose comprises a supply of vasodilator for one hour, for four hours,for eight hours for a normal night sleep, for 24 hours applied oncedaily, for 48 hours or longer, and the like. In practicing theinvention, one or more than one bandage can be on the skin at the sametime, and the bandages can be applied one after another.

Reservoir 22 comprises a gelled fluid, which latter term includesnaturally occurring and synthetic oils. The oils are selected from thegroup consisting essentially of inorganic and organic oils, such asmineral, nut, plant, sylvan and vegetable oils. In a preferredembodiment silicone fluid, also called silicone oils, is used forforming the reservoir. The silicone fluids have a range of viscositiesfrom 1 to 100,000 centistokes. Representative silicone fluids includedimethylsilicone fluid, methlphenylsiloxysilicone fluid,diphenylsiloxysilicone fluid, methylvinylsiloxysilicone fluid,polydimethylsiloxane fluid, and the like. Reservoir 22 contains arheological agent that imparts gelling properties to the fluid. Therheologic agents are selected from cellulosic, polysaccharide andsilicone agents. The polysaccharides include linear or branchedpolysaccharides such as agar, agarose, algin, sodium alginate,carrageenan, gum tragacanth, and the like. The cellulose agents includecellulose, cellulose derivatives, alkylcellulose, hydroxyalkylcellulosederivatives where the alkyl group is 1 to 7 carbons,carboxyalkylcellulose and the like. The silicone agents include fumedsilica, precipitated silica, amorphous silica, colloidal silicondioxide, fused silica, silica gel, and the like.

Release rate controlling membrane 24 is formed of polymers includingpolyolefins, polyamides, polyesters, ethylene-ethacrylate copolymer,segmented copolymer of butylene terephthalate 33% and polytetramethyleneether terephthalate 67%, segmented copolymer of propylene terephthatate58% and polytetramethylene ether terephthalate, block copolymer oftetramethylene terephthalate-polytetramethylene ether glycolterephthalate, ethylene-vinyl acetate copolymer, and the like. In anembodiment the bandage is provided with a protective cover held incontact by an adhesive with the reservoir. The cover is stripped fromthe bandage before it is positioned on the skin, whereon it administersfrom 10 μg to 400 μg of vasodilator per hour.

Another bandage that can be used for administering a vasodilatortopically is seen in FIG. 3. In FIG. 3, medical bandage 30 is seen incross-section and it comprises a backing member 31, a reservoir 32containing vasodilator 33 and an optional film of adhesive 34 forsecuring bandage 30 on a patient. Backing member 31 can be aluminiumfoil, polyethylene, Mylar® polyethylene terephthalate, a laminate ofpolyethylene terephthalate with an intermediate layer of aluminum foiland a layer of ionomer, Surlyn®, and the like. The same materials usedfor forming backing member 31 also can be used as a strippable cover,not shown, positioned over the reservoir and stripped free of bandage 30before use. Reservoir 30 comprises glycerol, polyvinyl alcohol, a watersoluble polymer with hydration sites selected from the group consistingof polyvinylpyrrolidone, agar, agarose and cellulose derivatives, water,40 to 60 mg of trinitroglycerol as the lactose triturate, for releasing5 mg of vasodilator over a 24 hour period. The medical bandage is heldin place by, for example, silicone adhesive, an elastic band, and thelike.

The pharmaceutical preparations for internal use include oral,sublingual and buccal dosage forms. The orally administered vasodilatorsinclude physiologically active vasodilators such as isosorbidedinitrate, nitroglycerin, pentaerythritol tetranitrate and the like.They can be used in dosage forms including capsules, tablets andsustained release forms. For example, isosorbide dinitrate can be madeinto capsules, timed release, containing 10 to 40 mg. tablets 5 to 20 mgand tablets, timed release 40 mg; erythrityl tetranitrate into tabletscontaining 5 to 15 mg; pentaerythritol tetranitrate as capsules, timedrelease, containing 30 and 80 mg and as tablets containing 10 and 20 mg;and nitroglycerin in capsules, plain and timed release 2.5, 6.5 and 9 mgand tablets 2.5 and 6.5 mg. For sublingual administration nitroglycerinis administered in doses up to 0.6 mg; for sublingual administration ofisosorbide dinitrate the dose is 2.5 to 5 mg; and erythrityltetranitrate the dose is 5 to 15 mg. Buccal administration uses a dosagecorresponding to sublingual administration for passing through themucosa and into the systemic circulation. The dosage form can beadministered in a single dose, in more than one dose by the same ordifferent internal routes, and in additional doses at successiveintervals.

The dosage forms are made by standard manufacturing procedures. Forexample, tablets are made by standard procedures such as mixing avasodilator such as nitroglycerin, inositol hexanitrate or the like withmannitol and magnesium stearate, and then compressing the mixture intotablets. A sustained release vasodilator medication is made by formingpellets of between 8 and 40 mesh size of an innocuous exipient such asmilk sugar, mannitol, sorbitol and the like, and then coating thepellets with a vasodilator such as nitroglycerin, mannitol hexanitrate,erythritol tetranitrate, pentaerythritol or the like. The pellets andthe vasodilator are mixed in a volatile liquid such as acetone, ether orthe like, and the liquid then evaporated, to yield coated particles. Therelative proportions of the pellets and medicament can vary, butgenerally about 1 part pellet to 3 parts of medicament can be used formaking the pharmaceutical composition. Next, a disintegratable coatingsuch as shellac, beeswax or the like is coated onto themedicament-pellets from an organic solvent such as acetone, and thecoated sustained release form placed in an oven to dry. Next, some ofsustained release coated pellets are mixed with pellets free of thedisintegratable coating and charged into a gelatin capsule to provideboth immediate and sustained release therapy. Internal dosage forms andprocedures for making dosage forms are described in Int. J. Pharm., Vol.1, pages 197 to 204, 1978; The Am. J. of Med., Vol. 65, pages 58 to 62,1978; AMA Drug Evaluations, pages 529 to 532, 1980; Remington'sPharmaceutical Science, 14th Edition, pages 1649 to 1698, 1970; and,U.S. Pat. No. 2,963,402.

The method of administering a vasodilator topically from a transdermaltherapeutic delivery system and internally from a pharmaceutical dosageform was demonstrated by the following study. The study was carried outwith 13 male patients with chronic, stable angina pectoris due toarteriosclerotic heart disease. Eight of the patients suffered amyocardial infarction before the study. The patients had the disease foran average of 4 years and an average of 18 anginal attacks per week. Thepatients had an average age of 55 years, an average height of 168 cm andand average weight of 73 kg. The transdermal delivery system used forthe study comprised an occlusive backing member, a reservoir adjacent tothe backing member comprising gelled, medical silicone fluid, nationalformulary colloidal silicon dioxide and nitroglycerin-lactose, a laminaadjacent to the reservoir comprising release rate controllingethylene-vinyl acetate copolymer having a vinyl acetate content of 9%,and an adhesive for holding the system on the skin. The systemsdelivered 40 μg/hr/cm² of nitroglycerin. Placebo systems were identicalwith nitroglycerin systems.

The study was conducted as a double-blind randomized cross-overcomparison of the nitroglycerin system and the placebo system. Thetreatment schedule comprised a group of 7 patients using the placebosystems for weeks 1 and 2 and then crossing over and using anitroglycerin system for weeks 3 and 4, and a second group of 6 patientsusing the nitroglycerin system for weeks 1 and 2 and then crossing overand using a placebo system for weeks 3 and 4. The patients were givenweekly check-ups and also underwent exercise tests. The exercise testingfollowed the procedure reported in Ann. Clin. Res., Vol. 3, pages 323 to332, 1971. At the initial consultations, the study proper commenced, thepatients were subjected to progressively increasing work-loads untilangina was provoked. All subsequent exercise tests were performed at thesame work-loads and under the same conditions.

The results of the study indicated, in all patients, anginal attackswere on the average of 60% less frequent during their 14 day period oftreatment with system releasing nitroglycerin, than during the placeboperiod. Nitroglycerin was administered internally, sublingually intablets containing up to 0.6 mg during the placebo and medicationperiods in response to anginal attacks. The results indicated patientstook on the average greater than 2 tablets of nitroglycerin daily duringthe placebo period, and an average of less than 1 tablet ofnitroglycerin daily during the medication period. The treatment withtransdermal delivery of nitroglycerin and internally administerednitroglycerin lessen internal administrations on the average 63% whencompared with the placebo period. Under medication, systolic bloodpressure during exercise was lowered by 7 to 15 mmHg and diastolicpressure by 5 to 8 mmHg, heart rate immediately after exercise was also3 to 11 beats/minute less than during placebo medication, and anginalattacks were less severe and of shorter duration.

While there has been described and pointed out features of the inventionas applied to presently preferred embodiments, those skilled in the artwill appreciate that various modifications, changes, additions andomissions of the method illustrated and described can be made withoutdeparting from the spirit of the invention.

We claim:
 1. A method for treating angina in a patient having angina bytransdermally and sublingually administering a drug to said patient fortreating angina, wherein the method comprises:(a) placing on the dermisof patient afflicted with angina a medical bandage comprising:(1) areservoir comprising a gel composition comprising: (i) an oil selectedfrom the group consisting of an inorganic oil and an organic oil, (ii) acellulosic means for gelling the oil, and (iii) a drug present in atherapeutically effective amount for treating angina; (2) a membraneadjacent to one surface of the reservoir, the membrane comprising acomposition that aids in releasing the drug from the reservoir overtime; (3) a backing member comprising a composition that issubstantially impermeable to the passage of drug adjacent to theopposite surface of the reservoir, which backing contacts the membrane;(b) admitting sublingually into the patient a pharmaceutical dosage formcomprising a drug useful for treating angina; and, (c) concomitentlyadministering the drug transdermally for treating angina in the patient.2. A method for treating angina in a patient having angina bytransdermally and sublingually administering a drug for treating anginato said patient, which method comprises:(a) placing on the dermis of apatient afflicted with angina a medical bandage comprising:(1) areservoir comprising a gel composition comprising: (i) an oil selectedfrom the group consisting of an inorganic oil and an organic oil, (ii)polysaccharide means for gelling the oil, and (iii) a drug present in atherapeutically effective amount for treating angina; (2) a membraneadjacent to one surface of the reservoir, the membrane comprising acomposition that aids in releasing the drug from the reservoir overtime; (3) a backing member comprising a composition that issubstantially impermeable to the passage of drug, and is in contactingrelation with the membrane; (b) admitting sublingually into the patienta pharmaceutical dosage form comprising a drug useful for treatingangina; and, (c) successively administering the drug transdermally fortreating angina in the patient.
 3. A method for treating angina in apatient having angina, which method comprises:(a) administering to thepatient sublingually a dosage form comprising a beneficial drug usefulfor treating angina; (b) administering to the patient transdermally froma medical bandage a drug useful for treating angina, which bandagecomprises:(1) a backing member comprising a composition that issubstantially impermeable to the passage of drug; (2) a reservoir incontact with the backing member, the reservoir comprising: a gelcomposition comprising silicone fluid, silicon dioxide and a drug usefulfor treating angina dispersed through the gel composition; (3) amembrane positioned opposite the backing member and adjacent to thereservoir, the membrane comprising a composition that aids in releasingdrug from the reservoir and is in contact with the backing member; and,(c) wherein the drug is administered sublingually and transdermally in atherapeutically effective amount to the patient for treating angina.